Reduced Brain Inflammation Research Articles

Hop bitter acids containing a \u03b2-carbonyl moiety prevent inflammation-induced cognitive decline via the vagus nerve and noradrenergic system

The prevention of age-related cognitive decline and dementia is becoming a high priority because of the rapid growth of aging populations. We have previously shown that hop bitter acids such as iso-α-acids (IAAs) and matured hop bitter acids (MHBAs) activate the vagus nerve and improve memory impairment. Moreover, supplements with MHBAs were shown to improve memory retrieval in older adults. However, the underlying mechanisms have not been entirely elucidated. We aimed to investigate the effects of MHBAs and the common β-tricarbonyl moiety on memory impairment induced by the activation of microglia and the loss of the noradrenergic system. MHBAs and a model compound with β-tricarbonyl moiety were administered to LPS-inoculated mice and 5 × FAD Alzheimer’s disease (AD) model mice, following the evaluation in behavioral tests and microglial activation. To evaluate the association of noradrenaline with MHBAs effects, mice treated with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), a noradrenergic neurotoxin that selectively damages noradrenergic projections from the locus coeruleus, were subjected to the behavioral evaluation. MHBAs reduced brain inflammation and improved LPS-induced memory impairment. A model compound possessing the β-tricarbonyl moiety improved the LPS-induced memory impairment and neuronal loss via the vagus nerve. Additionally, the protective effects of MHBAs on memory impairment were attenuated by noradrenaline depletion using DSP-4. MHBAs suppressed the activation of microglia and improved the memory impairment in 5 × FAD mice, which was also attenuated by noradrenaline depletion. Treatment with MHBAs increased cholecystokinin production from the intestinal cells. Generally, cholecystokinin activates the vagal nerve, which stimulate the noradrenergic neuron in the locus ceruleus. Taken together, our results reveal that food ingredients such as hop bitter acids with a β-tricarbonyl moiety suppress microglial activation and improve memory impairment induced by inflammation or AD pathology via the activation of the gut-brain axis and noradrenergic system. Supplements with hop bitter acids, including MHBAs, might be a novel approach for the prevention of cognitive decline and dementia.

Donepezil provides neuroprotective effects against brain injury and Alzheimer's pathology under conditions of cardiac ischemia/reperfusion injury

Cardiac ischemia/reperfusion (I/R) injury induces brain pathology. Donepezil, a well-known acetylcholine esterase (AChE) inhibitor, has been proven to exert neuroprotective effects against several neurodegenerative diseases. However, the comprehensive mechanism regarding the therapeutic potential of donepezil on the brain under cardiac I/R injury remains obscure. Here, we hypothesized that treatment with donepezil ameliorates brain pathology following cardiac I/R injury by decreasing blood brain barrier (BBB) breakdown, oxidative stress, neuroinflammation, mitochondrial dysfunction, mitochondrial dynamics imbalance, microglial activation, amyloid-beta (Aβ) accumulation, neuronal apoptosis, and dendritic spine loss. Forty-eight adult male Wistar rats were subjected to surgery for cardiac I/R injury. Then, rats were randomly divided into four groups to receive either (1) saline (vehicle group), donepezil 3 mg/kg via intravenously administered (2) before ischemia (pretreatment group), (3) during ischemia (ischemia group), or (4) at the onset of reperfusion (reperfusion group). At the end of cardiac I/R paradigm, the brains were evaluated for BBB breakdown, brain inflammation, oxidative stress, mitochondrial function, mitochondrial dynamics, microglial morphology, Aβ production, neuronal apoptosis, and dendritic spine density. Administration of donepezil at all time points equally showed an attenuation of brain damage in response to cardiac I/R injury, as indicated by increased expression of BBB junction protein, reduced brain inflammation and oxidative stress, improved mitochondrial function and mitochondrial dynamics, and alleviated Aβ accumulation and microglial activation, resulting in protection of neuronal apoptosis and preservation of dendritic spine number. These findings suggest that donepezil potentially protects brain pathology caused by cardiac I/R injury regardless the timing of treatment.

A pilot study investigating the effects of voluntary exercise on capillary stalling and cerebral blood flow in the APP/PS1 mouse model of Alzheimer's disease.

Exercise exerts a beneficial effect on the major pathological and clinical symptoms associated with Alzheimer’s disease in humans and mouse models of the disease. While numerous mechanisms for such benefits from exercise have been proposed, a clear understanding of the causal links remains elusive. Recent studies also suggest that cerebral blood flow in the brain of both Alzheimer’s patients and mouse models of the disease is decreased and that the cognitive symptoms can be improved when blood flow is restored. We therefore hypothesized that the mitigating effect of exercise on the development and progression of Alzheimer’s disease may be mediated through an increase in the otherwise reduced brain blood flow. To test this idea, we performed a pilot study to examine the impact of three months of voluntary wheel running in a small cohort of ~1-year-old APP/PS1 mice on short-term memory function, brain inflammation, amyloid deposition, and baseline cerebral blood flow. Our findings that exercise led to a trend toward improved spatial short-term memory, reduced brain inflammation, markedly increased neurogenesis in the dentate gyrus, and a reduction in hippocampal amyloid-beta deposits are consistent with other reports on the impact of exercise on the progression of Alzheimer’s related symptoms in mouse models. Notably, we did not observe any impact of wheel running on overall baseline blood flow nor on the incidence of non-flowing capillaries, a mechanism we recently identified as one contributing factor to cerebral blood flow deficits in mouse models of Alzheimer’s disease. Overall, our findings add to the emerging picture of differential effects of exercise on cognition and blood flow in Alzheimer’s disease pathology by showing that capillary stalling is not decreased following exercise.

Telmisartan Inhibits TNFα-Induced Leukocyte Adhesion by Blocking ICAM-1 Expression in Astroglial Cells but Not in Endothelial Cells.

Telmisartan is an angiotensin-II receptor blocker and acts as a selective modulator of peroxisome proliferator-activated receptor gamma (PPARγ). Several studies have demonstrated that telmisartan ameliorates depression and memory dysfunction and reduces brain inflammation. We hypothesized that the beneficial effects of telmisartan on brain could be due to modulation of the blood-brain barrier (BBB) function. Here, we examined the effect of telmisartan on tumor necrosis factor alpha (TNF-α)-induced expression of intercellular adhesion molecule 1 (ICAM-1) which plays an important role in leukocyte transcytosis through the BBB. Telmisartan blocked TNF-α-induced ICAM-1 expression and leukocyte adhesion in U87MG human glioma cells but showed no effect on human brain microvascular endothelial cells. In U87MG cells, a PPAR antagonist, GW9662 did not block the effect of telmisartan on ICAM1 expression but rather potentiated. Moreover, GW9662 caused no change in TNF-α-induced ICAM-1 expression, suggesting no implication of PPARγ in the telmisartan effect. Further studies showed that telmisartan blocked TNF-α-induced activation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and nuclear factor-kappa B (NF-κB). In contrast, inhibitors of JNK, ERK1/2 and NF-κB but not p38, blocked ICAM-1 expression induced by TNF-α. Thus, our findings suggest that the beneficial effect of telmisartan is likely due to the reduction of astrocytic ICAM1 expression and leukocytes adhesion to astrocytes, and that this response was mediated by the inhibition of JNK/ERK1/2/NF-κB activation and in the PPAR-independent manner. In conclusion, this study enhances our understanding of the mechanism by which telmisartan exerts the beneficial brain function.

Deletion of Voltage-Gated Calcium Channels in Astrocytes during Demyelination Reduces Brain Inflammation and Promotes Myelin Regeneration in Mice.

To determine whether Cav1.2 voltage-gated Ca2+ channels contribute to astrocyte activation, we generated an inducible conditional knock-out mouse in which the Cav1.2 α subunit was deleted in GFAP-positive astrocytes. This astrocytic Cav1.2 knock-out mouse was tested in the cuprizone model of myelin injury and repair which causes astrocyte and microglia activation in the absence of a lymphocytic response. Deletion of Cav1.2 channels in GFAP-positive astrocytes during cuprizone-induced demyelination leads to a significant reduction in the degree of astrocyte and microglia activation and proliferation in mice of either sex. Concomitantly, the production of proinflammatory factors such as TNFα, IL1β and TGFβ1 was significantly decreased in the corpus callosum and cortex of Cav1.2 knock-out mice through demyelination. Furthermore, this mild inflammatory environment promotes oligodendrocyte progenitor cells maturation and myelin regeneration across the remyelination phase of the cuprizone model. Similar results were found in animals treated with nimodipine, a Cav1.2 Ca2+ channel inhibitor with high affinity to the CNS. Mice of either sex injected with nimodipine during the demyelination stage of the cuprizone treatment displayed a reduced number of reactive astrocytes and showed a faster and more efficient brain remyelination. Together, these results indicate that Cav1.2 Ca2+ channels play a crucial role in the induction and proliferation of reactive astrocytes during demyelination; and that attenuation of astrocytic voltage-gated Ca2+ influx may be an effective therapy to reduce brain inflammation and promote myelin recovery in demyelinating diseases.SIGNIFICANCE STATEMENT Reducing voltage-gated Ca2+ influx in astrocytes during brain demyelination significantly attenuates brain inflammation and astrocyte reactivity. Furthermore, these changes promote myelin restoration and oligodendrocyte maturation throughout remyelination.

Changes in inflammation are related to depression and amount of aerobic exercise in first episode schizophrenia.

Elevated levels of pro-inflammatory cytokines have been reported in meta-analyses of multi-episode schizophrenia patients when compared to controls. However, little is known about whether these same relationships are present in the early course of schizophrenia. To assess first episode schizophrenia patients for depression and to assay blood samples collected at baseline and at 6 months for interleukin-6 (IL-6). Trained raters used the Brief Psychiatric Rating Scale to assess depressive symptoms and a standard lab assay kit to assess for IL-6 levels in plasma. Decreases in pro-inflammatory IL-6 levels were significantly related to decreases in depressive symptoms. Within a subset of patients in a 6-month aerobic exercise protocol, the number of exercise sessions completed was significantly correlated with the amount of decrease in IL-6. The reductions observed in IL-6 with aerobic exercise suggest exercise is a promising intervention to reduce brain inflammation effects in schizophrenia patients.

Carbon monoxide poisoning can act as a stress test to reveal underlying coronary artery disease: case report

Despite established exposure limits and safety standards as well as the availability of carbon monoxide (CO) alarms, each year 50,000 people in the United States visit emergency departments for CO poisoning. Carbon monoxide poisoning can occur from brief exposures to high levels of CO or from longer exposures to lower levels. Common symptoms can include headaches, nausea and vomiting, dizziness, general malaise, and altered mental status. Some patients may have chest pain, shortness of breath, and myocardial ischemia, and may require mechanical ventilation and treatment of shock. Individuals poisoned by CO often develop brain injury manifested by neurological problems, including cognitive sequelae, anxiety and depression, persistent headaches, dizziness, sleep problems, motor weakness, vestibular and balance problems, gaze abnormalities, peripheral neuropathies, hearing loss, tinnitus, Parkinsonian-like syndrome, and other problems. In addition, some will have cardiac issues or other ailments. While breathing oxygen hastens the removal of carboxyhemoglobin (COHb), hyperbaric oxygen (HBO2) hastens COHb elimination and favorably modulates inflammatory processes instigated by CO poisoning, an effect not observed with breathing normobaric oxygen. Hyperbaric oxygen improves mitochondrial function, inhibits lipid peroxidation transiently, impairs leukocyte adhesion to injured microvasculature, and reduces brain inflammation caused by the CO-induced adduct formation of myelin basic protein. Based upon three supportive randomized clinical trials in humans and considerable evidence from animal studies, HBO2 should be considered for all cases of acute symptomatic CO poisoning. Hyperbaric oxygen is indicated for CO poisoning complicated by cyanide poisoning, often concomitantly with smoke inhalation.

Mechanism of Dexmedetomidine on Brain Injury in Mice with Sepsis

In order to explore the mechanism of dexmedetomidine on brain damage in sepsis, mice were used to detect the staining of cells with hematoxylin-eosin and terminal-deoxynucleotidyl transferase mediated nick end labeling, the content of Evans blue in the brain, and the expression of TNF-α, IL-1β, malonaldehyde, reactive oxygen species, Bcl-2, Bax, cleaved caspase-3 were explored to understand possible mechanism of dexmedetomidine brain protection. The results showed that firstly, dexmedetomidine could attenuate the abnormal morphological changes of neurons in the brain and neuronal apoptosis, secondly, dexmedetomidine could attenuate the expression of TNF-α, IL-1β, MDA, ROS, Bcl-2, Bax, cleaved caspase-3 and iNOS. In summary, the cerebral protection mechanism of dexmedetomidine in septic mice might be connected with reducing the blood brain barrier destruction, reducing brain inflammation and oxidative stress levels, as well as inhibition of apoptosis by altering the expression of Bax, Bcl-2, and cleaved caspase-3. Despite some shortcomings in this investigation, these results still provide clear guidance for future research.

Recent advances in understanding multiple sclerosis.

Emerging data point to important contributions of both autoimmune inflammation and progressive degeneration in the pathophysiology of multiple sclerosis (MS). Unfortunately, after decades of intensive investigation, the fundamental cause remains unknown. A large body of research on the immunobiology of MS has resulted in a variety of anti-inflammatory therapies that are highly effective at reducing brain inflammation and clinical/radiological relapses. However, despite potent suppression of inflammation, benefit in the more important and disabling progressive phase is extremely limited; thus, progressive MS has emerged as the greatest challenge for the MS research and clinical communities. Data obtained over the years point to a complex interplay between environment (e.g., the near-absolute requirement of Epstein–Barr virus exposure), immunogenetics (strong associations with a large number of immune genes), and an ever more convincing role of an underlying degenerative process resulting in demyelination (in both white and grey matter regions), axonal and neuro-synaptic injury, and a persistent innate inflammatory response with a seemingly diminishing role of T cell–mediated autoimmunity as the disease progresses. Together, these observations point toward a primary degenerative process, one whose cause remains unknown but one that entrains a nearly ubiquitous secondary autoimmune response, as a likely sequence of events underpinning this disease. Here, we briefly review what is known about the potential pathophysiological mechanisms, focus on progressive MS, and discuss the two main hypotheses of MS pathogenesis that are the topic of vigorous debate in the field: whether primary autoimmunity or degeneration lies at the foundation. Unravelling this controversy will be critically important for developing effective new therapies for the most disabling later phases of this disease.

The glucagon-like peptide-1 receptor agonist reduces inflammation and blood-brain barrier breakdown in an astrocyte-dependent manner in experimental stroke

BackgroundPreserving the integrity of the blood-brain barrier (BBB) is beneficial to avoid further brain damage after acute ischemic stroke (AIS). Astrocytes, an important component of the BBB, promote BBB breakdown in subjects with AIS by secreting inflammatory factors. The glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) protects the BBB and reduces brain inflammation from cerebral ischemia, and GLP-1R is expressed on astrocytes. However, the effect of Ex-4 on astrocytes in subjects with AIS remains unclear.MethodsIn the present study, we investigated the effect of Ex-4 on astrocytes cultured under oxygen-glucose deprivation (OGD) plus reoxygenation conditions and determined whether the effect influences bEnd.3 cells. We used various methods, including permeability assays, western blotting, immunofluorescence staining, and gelatin zymography, in vitro and in vivo.ResultsEx-4 reduced OGD-induced astrocyte-derived vascular endothelial growth factor (VEGF-A), matrix metalloproteinase-9 (MMP-9), chemokine monocyte chemoattractant protein-1 (MCP-1), and chemokine C-X-C motif ligand 1 (CXCL-1). The reduction in astrocyte-derived VEGF-A and MMP-9 was related to the increased expression of tight junction proteins (TJPs) in bEnd.3 cells. Ex-4 improved neurologic deficit scores, reduced the infarct area, and ameliorated BBB breakdown as well as decreased astrocyte-derived VEGF-A, MMP-9, CXCL-1, and MCP-1 levels in ischemic brain tissues from rats subjected to middle cerebral artery occlusion. Ex-4 reduced the activation of the JAK2/STAT3 signaling pathway in astrocytes following OGD.ConclusionBased on these findings, ischemia-induced inflammation and BBB breakdown can be improved by Ex-4 through an astrocyte-dependent manner.

Inhibition of Upf2-Dependent Nonsense-Mediated Decay Leads to Behavioral and Neurophysiological Abnormalities by Activating the Immune Response

In humans, disruption of nonsense-mediated decay (NMD) has been associated with neurodevelopmental disorders (NDDs) such as autism spectrum disorder and intellectual disability. However, the mechanism by which deficient NMD leads to neurodevelopmental dysfunction remains unknown, preventing development of targeted therapies. Here we identified novel protein-coding UPF2 (UP-Frameshift 2) variants in humans with NDD, including speech and language deficits. In parallel, we found that mice lacking Upf2 in the forebrain (Upf2 fb-KO mice) show impaired NMD, memory deficits, abnormal long-term potentiation (LTP), and social and communication deficits. Surprisingly, Upf2 fb-KO mice exhibit elevated expression of immune genes and brain inflammation. More importantly, treatment with two FDA-approved anti-inflammatory drugs reduced brain inflammation, restored LTP and long-term memory, and reversed social and communication deficits. Collectively, our findings indicate that impaired UPF2-dependent NMD leads to neurodevelopmental dysfunction andsuggest that anti-inflammatory agents may prove effective for treatment of disorders with impaired NMD.

Supplementation with Nicotinamide Riboside Reduces Brain Inflammation and Improves Cognitive Function in Diabetic Mice.

The purpose of this study is to investigate whether nicotinamide riboside (NR) can improve inflammation and cognitive function in diabetic mice. ICR male mice were fed for 14 weeks with either high-fat chow diet (HF, 60% kcal fat) or standard chow diet (CON, 10% kcal fat). HF, streptozotocin, and nicotinamide were used to induce hyperglycemia. NR or vehicle was delivered via stomach gavage for six weeks. Oral glucose tolerance test, Y-maze test, and nest construction test were conducted before and after the NR treatment period. NR treatment induced down-regulation of NLRP3, ASC, and caspase-1. NR reduced IL-1 expression significantly by 50% in whole brains of hyperglycemic mice. Other inflammatory markers including TNF-α and IL-6 were also attenuated by NR. Brain expression of amyloid-β precursor protein and presenilin 1 were reduced by NR. In addition, NR induced significant reduction of amyloid-β in whole brains of diabetic mice. NR treatment restored hyperglycemia-induced increases in brain karyopyknosis to the levels of controls. Nest construction test showed that NR improved hippocampus functions. Spatial recognition memory and locomotor activity were also improved by NR supplementation. These findings suggest that NR may be useful for treating cognitive impairment by inhibiting amyloidogenesis and neuroinflammation.

Role of NS1 and TLR3 in Pathogenesis and Immunity of WNV.

West Nile Virus (WNV) is a mosquito-transmitted flavivirus which causes encephalitis especially in elderly and immunocompromised individuals. Previous studies have suggested the protective role of the Toll-like receptor 3 (TLR3) pathway against WNV entry into the brain, while the WNV non-structural protein 1 (NS1) interferes with the TLR3 signaling pathway, besides being a component of viral genome replication machinery. In this study, we investigated whether immunization with NS1 could protect against WNV neuroinvasion in the context of TLR3 deficiency. We immunized mice with either an intact or deleted TLR3 system (TLR3KO) with WNV envelope glycoprotein (gE) protein, NS1, or a combination of gE and NS1. Immunization with gE or gE/NS1, but not with NS1 alone, induced WNV neutralizing antibodies and protected against WNV brain invasion and inflammation. The presence of intact TLR3 signaling had no apparent effect on WNV brain invasion. However, mock-immunized TLR3KO mice had higher inflammatory cell invasion upon WNV brain infection than NS1-immunized TLR3KO mice and wild type mice. Thus, immunization against NS1 may reduce brain inflammation in a context of TLR3 signaling deficiency.

Post-stroke treatment with argon attenuated brain injury, reduced brain inflammation and enhanced M2 microglia/macrophage polarization: a randomized controlled animal study

BackgroundIn recent years, argon has been shown to exert neuroprotective effects in an array of models. However, the mechanisms by which argon exerts its neuroprotective characteristics remain unclear. Accumulating evidence imply that argon may exert neuroprotective effects via modulating the activation and polarization of microglia/macrophages after ischemic stroke. In the present study, we analyzed the underlying neuroprotective effects of delayed argon application until 7 days after reperfusion and explored the potential mechanisms.MethodsTwenty-one male Wistar rats underwent transient middle cerebral artery occlusion or sham surgery randomly for 2 h using the endoluminal thread model. Three hours after transient middle cerebral artery occlusion induction and 1 h after reperfusion, animals received either 50% vol Argon/50% vol O2 or 50% vol N2/50% vol O2 for 1 h. The primary outcome was the 6-point neuroscore from 24 h to d7 after reperfusion. Histological analyses including infarct volume, survival of neurons (NeuN) at the ischemic boundary zone, white matter integrity (Luxol Fast Blue), microglia/macrophage activation (Iba1), and polarization (Iba1/Arginase1 double staining) on d7 were conducted as well. Sample size calculation was performed using nQuery Advisor + nTerim 4.0. Independent t test, one-way ANOVA and repeated measures ANOVA were performed, respectively, for statistical analysis (SPSS 23.0).ResultsThe 6-point neuroscore from 24 h to d7 after reperfusion showed that tMCAO Ar group displayed significantly improved neurological performance compared to tMCAO N2 group (p = 0.026). The relative numbers of NeuN-positive cells in the ROIs of tMCAO Ar group significantly increased compared to tMCAO N2 group (p = 0.010 for cortex and p = 0.011 for subcortex). Argon significantly suppressed the microglia/macrophage activation as revealed by Iba1 staining (p = 0.0076) and promoted the M2 microglia/macrophage polarization as revealed by Iba1/Arginase 1 double staining (p = 0.000095).ConclusionsArgon administration with a 3 h delay after stroke onset and 1 h after reperfusion significantly alleviated neurological deficit within the first week and preserved the neurons at the ischemic boundary zone 7 days after stroke. Moreover, argon reduced the excessive microglia/macrophage activation and promoted the switch of microglia/macrophage polarization towards the anti-inflammatory M2 phenotype. Studies making efforts to further elucidate the protective mechanisms and to benefit the translational application are of great value.

Promoting the Assessment of Physical Activity and Cardiorespiratory Fitness in Assessing the Role of Vascular Risk on Cognitive Decline in Older Adults.

The world population has been experiencing significant aging processes that have resulted in rising proportions of older persons in the total population since the mid-twentieth century. It is estimated that by 2025 there will be 1.2 billion people over 60 years of age and by 2050 there will be 2 billion, with 80% in developing countries (World Health Organization, 2011) Moreover, the recent (Alzheimer's Disease International., 2018) indicates that over 50 million people live with dementia worldwide, which is expected to exceed 152 million by 2050. There is no known cure for dementia and, thus, preventative strategies are of great importance. In fact, the annual cost of dementia care was expected to exceed $1 trillion by 2018, thereby, primary prevention is currently considered a potential tool to delay the disease onset by modulating modifiable risk factors. In fact, it has been suggested around 35% of dementia is attributable to a combination of nine modifiable risk factors, including education, hypertension, obesity, hearing loss, depression, diabetes, physical inactivity, smoking, and social isolation (Livingston et al., 2017). In line with that, three potential brain mechanisms through which preventative strategies may reduce dementia risk are: (a) reduced brain damage (vascular, neurotoxic and oxidative stress), (b) reduced brain inflammation, and (c) increased brain cognitive reserve with greater physical activity (PA) and exercise suggested as a common factor to promote all these mechanisms (Livingston et al., 2017). Therefore, greater PA and fitness (especially cardiorespiratory fitness, CRF) are currently considered key factors to promote in the prevention of cognitive decline and dementia (Kennedy et al., 2017; Livingston et al., 2017; Muller et al., 2017). Moreover, these key factors not only directly affecting cognitive decline and dementia, but also have effect through their mediation effects on other related risk factors, such as hypertension, obesity, depression, and diabetes (Chase et al., 2009; Kokkinos et al., 2017; Celis-Morales et al., 2018; Chekroud et al., 2018; Ortega et al., 2018). Particularly well-established in the literature is the role of PA and CRF on cardiovascular (CV) risk factors and diseases (CVD), as well as mortality (Blair et al., 1998; Jimenez-Pavon et al., 2016; Ortega et al., 2018). However, studies analyzing the role of vascular risk on cognitive decline have been based solely upon the use of the Framingham Heart Study general cardiovascular disease score (i.e., Framingham Risk Score (FRS) (Eldholm et al., 2018; Rabin et al., 2018), and no studies have investigated the potential mediation effect of PA and CRF on the vascular risk of cognitive decline and dementia. Hence, we believe that to better understand the relationship between vascular risk and cognitive decline, assessment of PA and CRF should be included when determining an individual's vascular risk factors. Therefore, the purpose of this opinion article is to encourage the assessment of PA and fitness, at least CRF, when studying the role of vascular risk on cognitive decline.

Intranasal Delivery of Mesenchymal Stromal Cells Protects against Neonatal Hypoxic⁻Ischemic Brain Injury.

Cerebral palsy (CP) is a permanent motor disorder that results from brain injury and neuroinflammation during the perinatal period. Mesenchymal stromal cells (MSCs) have been explored as a therapy in multiple adult neuroinflammatory conditions. Our study examined the therapeutic benefits of intranasal delivery of human umbilical cord tissue (UC) derived-MSCs in a rat model of neonatal hypoxic–ischemic (HI) brain injury. To do this, HI was performed on postnatal day 10 Sprague-Dawley rat pups via permanent ligation of the left carotid artery, followed by a hypoxic challenge of 8% oxygen for 90 min. A total of 200,000 UC-MSCs (10 million/kg) were administered intranasally 24 h post-HI. Motor control was assessed after seven days, followed by post-mortem. Analysis included brain immunohistochemistry, gene analysis and serum cytokine measurement. Neonatal HI resulted in brain injury with significant loss of neurons, particularly in the hippocampus. Intranasal administration of UC-MSCs significantly reduced the loss of brain tissue and increased the number of hippocampal neurons. HI significantly upregulated brain inflammation and expression of pro-inflammatory cytokines, while intranasal UC-MSCs significantly reduced markers of neuroinflammation. This study demonstrated that a clinically relevant dose (10 million/kg) of UC-MSCs was neuroprotective following HI by restoring neuronal cell numbers and reducing brain inflammation. Therefore, intranasal delivery of UC-MSCs may be an effective therapy for neonatal brain injury.

Group A Streptococcus Subcutaneous Infection-Induced Central Nervous System Inflammation Is Attenuated by Blocking Peripheral TNF.

Group A streptococcus (GAS) infection causes a strong inflammatory response associated with cytokine storms, leading to multiorgan failure, which is characterized as streptococcal toxic shock syndrome. However, little is known about GAS subcutaneous infection-mediated brain inflammation. Therefore, we used a bioluminescent GAS strain and reporter mice carrying firefly luciferase under transcriptional control of the nuclear factor-kappa B (NF-κB) promoter to concurrently monitor the host immune response and bacterial burden in a single mouse. Notably, in addition to the subcutaneous inoculation locus at the back of mice, we detected strong luminescence signals from NF-κB activation and increased inflammatory cytokine production in the brain, implying the existence of central nervous system inflammation after GAS subcutaneous infection. The inflamed brain exhibited an increased expression of glial fibrillary acidic protein and nicotinamide adenine dinucleotide phosphate oxidase components and greater microglial activation and blood–brain barrier (BBB) disruption. Furthermore, Fluoro-Jade C positive cells increased in the brain, indicating that neurons underwent degeneration. Peripheral tumor necrosis factor (TNF), which contributes to pathology in brain injury, was elevated in the circulation, and the expression of its receptor was also increased in the inflamed brain. Blockage of peripheral TNF effectively reduced brain inflammation and injury, thereby preventing BBB disruption and improving survival. Our study provides new insights into GAS-induced central nervous system inflammation, such as encephalopathy, which can be attenuated by circulating TNF blockage.

Oxidation of KCNB1 channels in the human brain and in mouse model of Alzheimer\u2019s disease

Oxidative modification of the voltage-gated K+ channel subfamily B member 1 (KCNB1, Kv2.1) is emerging as a mechanism of neuronal vulnerability potentially capable of affecting multiple conditions associated with oxidative stress, from normal aging to neurodegenerative disease. In this study we report that oxidation of KCNB1 channels is exacerbated in the post mortem brains of Alzheimer’s disease (AD) donors compared to age-matched controls. In addition, phosphorylation of Focal Adhesion kinases (FAK) and Src tyrosine kinases, two key signaling steps that follow KCNB1 oxidation, is also strengthened in AD vs. control brains. Quadruple transgenic mice expressing a non-oxidizable form of KCNB1 in the 3xTg-AD background (APPSWE, PS1M146V, and tauP301L), exhibit improved working memory along with reduced brain inflammation, protein carbonylation and intraneuronal β-amyloid (Aβ) compared to 3xTg-AD mice or mice expressing the wild type (WT) KCNB1 channel. We conclude that oxidation of KCNB1 channels is a mechanism of neuronal vulnerability that is pervasive in the vertebrate brain.

Aquaporin-4 deletion ameliorates hypoglycemia-induced BBB permeability by inhibiting inflammatory responses

BackgroundSevere hypoglycemia induces brain edema by upregulating aquaporin-4 (AQP4) expression and by degrading tight junctions. Acute severe hypoglycemia induces a proinflammatory environment that may contribute to a disruption in the epithelial barrier by decreasing tight junction protein expression. Interestingly, the altered AQP4 expression has been considered to play a critical role in neuroinflammation during acute brain injury. It has been shown that AQP4 deletion reduces brain inflammation in AQP4-null mice after intracerebral LPS injection. However, the effect of AQP4 deletion regarding protection against hypoglycemia-induced blood-brain barrier (BBB) breakdown is unknown.MethodsAn acute severe hypoglycemic stress model was established via injection of 4 unit/kg body weight of insulin. Evans blue (EB) staining and water measurement were used to assess BBB permeability. Western blot, reverse transcription polymerase chain reaction, and immunofluorescence were used to detect the expression of related proteins. The production of cytokines was assessed via enzyme-linked immunosorbent assay.ResultsHypoglycemia-induced brain edema and BBB leakage were reduced in AQP4−/− mice. AQP4 deletion upregulated PPAR-γ and inhibited proinflammatory responses. Moreover, knockdown of aquaporin-4 by small interfering RNA in astrocytes co-cultured with endothelial cells effectively reduced transendothelial permeability and degradation of tight junctions. Treatment with PPAR-γ inhibitors showed that upregulation of PPAR-γ was responsible for the protective effect of AQP4 deletion under hypoglycemic conditions.ConclusionsOur data suggest that AQP4 deletion protects BBB integrity by reducing inflammatory responses due to the upregulation of PPAR-γ expression and attenuation of proinflammatory cytokine release. Reduction in AQP4 may be protective in acute severe hypoglycemia.

Central Nervous System Inflammation and Infection during Early, Nonaccelerated Simian-Human Immunodeficiency Virus Infection in Rhesus Macaques

ABSTRACTStudies utilizing highly pathogenic simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) have largely focused on the immunopathology of the central nervous system (CNS) during end-stage neurological AIDS and SIV encephalitis. However, this may not model pathophysiology in earlier stages of infection. In this nonaccelerated SHIV model, plasma SHIV RNA levels and peripheral blood and colonic CD4+ T cell counts mirrored early human immunodeficiency virus (HIV) infection in humans. At 12 weeks postinfection, cerebrospinal fluid (CSF) detection of SHIV RNA and elevations in IP-10 and MCP-1 reflected a discrete neurovirologic process. Immunohistochemical staining revealed a diffuse, low-level CD3+ CD4− cellular infiltrate in the brain parenchyma without a concomitant increase in CD68/CD163+ monocytes, macrophages, and activated microglial cells. Rare SHIV-infected cells in the brain parenchyma and meninges were identified by RNAScope in situ hybridization. In the meninges, there was also a trend toward increased CD4+ infiltration in SHIV-infected animals but no differences in CD68/CD163+ cells between SHIV-infected and uninfected control animals. These data suggest that in a model that closely recapitulates human disease, CNS inflammation and SHIV in CSF are predominantly mediated by T cell-mediated processes during early infection in both brain parenchyma and meninges. Because SHIV expresses an HIV rather than SIV envelope, this model could inform studies to understand potential HIV cure strategies targeting the HIV envelope.IMPORTANCE Animal models of the neurologic effects of HIV are needed because brain pathology is difficult to assess in humans. Many current models focus on the effects of late-stage disease utilizing SIV. In the era of antiretroviral therapy, manifestations of late-stage HIV are less common. Furthermore, new interventions, such as monoclonal antibodies and therapeutic vaccinations, target HIV envelope. We therefore describe a new model of central nervous system involvement in rhesus macaques infected with SHIV expressing HIV envelope in earlier, less aggressive stages of disease. Here, we demonstrate that SHIV mimics the early clinical course in humans and that early neurologic inflammation is characterized by predominantly T cell-mediated inflammation accompanied by SHIV infection in the brain and meninges. This model can be utilized to assess the effect of novel therapies targeted to HIV envelope on reducing brain inflammation before end-stage disease.